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Experimental Therapeutics

APX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in Experimental Coccidioides immitis Pneumonia

Suganya Viriyakosol, Mili Kapoor, Sharon Okamoto, Jonathan Covel, Quinlyn A. Soltow, Michael Trzoss, Karen Joy Shaw, Joshua Fierer
Suganya Viriyakosol
aVA Healthcare, San Diego, California, USA
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Mili Kapoor
bAmplyx Pharmaceuticals, San Diego, California, USA
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Sharon Okamoto
cDivision of Infectious Diseases, Department of Medicine, UC San Diego School of Medicine, San Diego, California, USA
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Jonathan Covel
bAmplyx Pharmaceuticals, San Diego, California, USA
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Quinlyn A. Soltow
bAmplyx Pharmaceuticals, San Diego, California, USA
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Michael Trzoss
bAmplyx Pharmaceuticals, San Diego, California, USA
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Karen Joy Shaw
bAmplyx Pharmaceuticals, San Diego, California, USA
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Joshua Fierer
aVA Healthcare, San Diego, California, USA
bAmplyx Pharmaceuticals, San Diego, California, USA
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DOI: 10.1128/AAC.01715-18
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    FIG 1

    Structures of Gwt1 inhibitors.

  • FIG 2
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    FIG 2

    Efficacy of APX001 in a murine model of coccidioidomycosis. Mice were infected intranasally with C. immitis RS arthroconidia and 50 mg/kg of APX001 was administered twice daily for 5 days beginning 7 days postinfection. Mice were sacrificed on day 13, 1 day after the last day of treatment, and colony counts were assessed from the lung and spleen. Each symbol represents one mouse. The horizontal lines show the geometric mean and SEM for the lung and spleen colony counts (CFU). Horizontal lines in the weight panel correspond to the calculated mean weight. The differences in mean weight of treated and control mice on days 11 and 13 were analyzed by two-way ANOVA (GraphPad Prism) and were highly significant (P < 0.001).

  • FIG 3
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    FIG 3

    ABT alone has no antifungal effect in mice. Infected mice were treated with a single daily dose of ABT for 5 days and sacrificed on day 13, the day after the last ABT dose. Fungal colony counts were log transformed. Geometric mean CFU/organ values ± the SEM were calculated and compared using an unpaired t test (Prism, v7.01). The mean weights ± the SEM were calculated, and there was no significant difference in the weights of untreated and ABT-treated mice on day 15 after infection.

  • FIG 4
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    FIG 4

    Reduction in fungal burden upon treatment with three Gwt1 prodrugs in a mouse model of pulmonary coccidioidomycosis. Mice were infected and treated as in Fig. 2, except that mice were pretreated with 50 mg/kg ABT by oral gavage 2 h prior to the administration of APX prodrugs or buffer starting 7 days after infection. Mice were weighed at the start and conclusion of the experiment and were sacrificed 1 day after their last dose. After log10 transformation, values for the geometric mean CFU/organ ± the SEM were calculated and compared using an unpaired t test (Prism, v7.01). If there were >2 groups, the differences in the means of treated and control groups were compared using Dunnett’s ANOVA test. A P value of ≤0.05 was considered statistically significant.

  • FIG 5
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    FIG 5

    Reduction in fungal burden upon treatment with APX001 and APX2097 in comparison to fluconazole. Mice were infected and treated with the ABT and APX prodrugs as in Fig. 3. Fluconazole was administered orally twice daily. Values for the geometric mean CFU/organ ± the SEM were calculated and compared using a paired t test (Prism, v7.01). If there were >2 groups, the differences in the means of treated and control groups were compared using Dunnett’s ANOVA test. All of the treatment groups had significant lower colony counts than the untreated control in lungs and spleen (P < 0.001). Only the untreated mice had a statistically significant eight loss on day 13 after infection compared to their starting weight (P = 0.006).

  • FIG 6
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    FIG 6

    Histological analysis of lung tissue sections in control versus APX001- and APX2097-treated mice. Mice were infected with C. immitis RS as described in Materials and Methods and then treated once daily with 50 mg/kg ABT plus APX001 or APX2097 at 26 mg/kg for 5 days. Control mice received only ABT. Lungs were removed a few hours after the last dose, fixed in glutaraldehyde, and then stained with PAS prior to microscopic examination (×20 magnification). (A) The control lungs showed many spherules in all stages of development and a myriad of endospores from ruptured spherules, surrounded by acute and chronic inflammatory cells. (B) APX001-treated mice had many small, immature spherules that were primarily inside macrophages. There were no fully grown spherules and few if any endospores. (C) The lungs of APX2097-treated mice had an appearance similar to the lungs of APX001-treated mice.

  • FIG 7
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    FIG 7

    Comparison of Kaplan-Meir survival curves and end-of-treatment weights of mice treated with APX001, APX2097, or fluconazole compared to untreated controls. Mice were infected and treated as described in Fig. 3. The arrows show the days of treatment. Kaplan-Meir survival curves were compared by log rank analysis (Prism, v7.01). All three treatment groups survived significantly longer than the control mice. Differences between the three treatment groups was also significant. The mean body weights of the three treatment groups and the untreated control on day 14 posttreatment were compared by ANOVA (Tukey’s multiple-comparison test; Prism, v7.01). There were no significant differences in the weights of fluconazole-, APX001-, and APX2097-treated mice. *, P < 0.01 for both graphs.

Tables

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  • TABLE 1

    In vitro susceptibility profiles

    StrainMEC (μg/ml), APX001AMIC (μg/ml)a
    APX001AFLCAMBPOS
    C. immitis RS0.002–0.0048>160.1250.06–0.125
    C. posadasii C7350.0040.03>160.250.06–0.125
    C. posadasii Silvera0.0088>160.250.03
    • ↵a The MIC value was read at 100% inhibition. FLC, fluconazole; AMB, amphotericin B; POS, posaconazole.

  • TABLE 2

    Activity of Gwt1 inhibitors versus C. immitis and C. posadasii

    Strain or parameterSourceMEC (μg/ml)MIC (μg/ml)
    APX001AAPX2020APX2041POS
    C. immitis
     RSLab0.002–0.004a0.002–0.0040.002–0.0040.06–0.125
     B2358CDC0.0040.0040.0001250.016
     F40Clinical0.0040.0020.0010.125
     F1Clinical0.0020.0010.0010.125
     UCSD2Clinical0.0010.0010.000250.125
    C. posadasii
     F6Clinical0.0160.0040.0010.125
     SilveraLab0.0080.0080.0040.03
     F5Clinical0.0080.0040.0010.016
     C735Lab0.0040.0020.0020.06–0.125
     D2AClinical0.0040.0020.0010.03
    Parameters
     GM0.0040.0020.0010.054
     MEC90/MIC900.0080.0040.0020.125
    • ↵a The lower value of the susceptibility range was used to calculate the geometric mean (GM) and 90% minimal effective concentration (MEC90).

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APX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in Experimental Coccidioides immitis Pneumonia
Suganya Viriyakosol, Mili Kapoor, Sharon Okamoto, Jonathan Covel, Quinlyn A. Soltow, Michael Trzoss, Karen Joy Shaw, Joshua Fierer
Antimicrobial Agents and Chemotherapy Jan 2019, 63 (2) e01715-18; DOI: 10.1128/AAC.01715-18

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APX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in Experimental Coccidioides immitis Pneumonia
Suganya Viriyakosol, Mili Kapoor, Sharon Okamoto, Jonathan Covel, Quinlyn A. Soltow, Michael Trzoss, Karen Joy Shaw, Joshua Fierer
Antimicrobial Agents and Chemotherapy Jan 2019, 63 (2) e01715-18; DOI: 10.1128/AAC.01715-18
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KEYWORDS

1-aminobenzotriazole
APX001
APX001A
Coccidioides
GPI anchor biosynthesis
Gwt1
antifungal therapy

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